Zusammenfassung
Die Grundlage der Antigenvariation bei Plasmodium falciparum ist die koordinierte Expression der var-Genfamilie. Jeder Parasit besitzt 60 verschiedene var-Gene, von denen jedoch nur ein Gen exprimiert wird. Die 60 Mitglieder der var-Genfamilie kodieren für 60 verschiedene Proteine, die als Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) bezeichnet werden. PfEMP1-Proteine befinden sich auf der Oberfläche des infizierten Erythrozyten. Zur Antigenvariation kommt es durch Veränderungen in der var-Genexprimierung und der daraus resultierenden Veränderung der Erythrozytenoberfläche. In den letzten Jahren ist es zu bemerkenswerten Fortschritten im Verständnis der Regulation der var-Genfamilie gekommen. Hierbei konnte klar gezeigt werden, dass die Kontrolle dieser Genfamilie durch ein komplexes System koordiniert wird. Im Einzelnen konnten die folgenden verschiedenen Regulationselemente identifiziert werden: das var-Gen Intron und der var-Gen Promoter, Chromatinveränderungen sowie ein Zellkernkompartiment für die Transkription von var-Genen. Es konnte ebenso gezeigt werden, dass die var-Genexprimierung über längere Zeiträume relativ stabil ist. Die meisten der aktuellen Fortschritte wurden durch Experimente mit Labor-Parasitenstämmen erzielt. Dies wirft zwei zentrale Fragen auf: 1. Entspricht die var-Genexprimierung bei Laborstämmen der var-Genexprimierung bei Feldisolaten? 2. Wie beeinflusst das Immunsystem die var-Genexprimierung in natürlichen Infektionen? Um diesen Fragen gerecht zu werden, untersuchen wir die Antigenvaration bei Parasiten aus Lambaréné, Gabun.
Summary
Antigenic variation in Plasmodium falciparum malaria is mediated by the multicopy var gene gene family. Each parasite carries approximately 60 different var genes. A system of mutually exclusive expression ensures that only one gene is expressed in each individual cell. This ensures that only 1 of the 60 variants is exposed to the immune system. Switches in var gene expression result in antigenic variation. During recent years there has been a remarkable progress in the understanding of the mechanisms that regulate var gene expression. Genetic elements such as the var gene intron, chromatin modifications and nuclear repositioning have all been implicated in the control of this large and diverse gene family. It has also been shown that var gene expression in clonal cultures is relatively stable over long periods of time, suggesting that an imprinted epigenetic program coordinates the expression of the gene family. Most of the recent advances in var gene biology have been generated through experiments with laboratory adapted parasite lines. This raises 2 central questions: 1. Does var gene expression in laboratory isolates resemble var gene expression in field isolates? 2. How does the immune system influence var gene expression in natural infections? To start to address these questions, we embarked on a series of experiments studying var gene expression in parasites recently obtained from asymptomatically infected adults from Lambaréné, Gabon.
References
Miller LH, Good MF, Milon G (1994) Malaria pathogenesis. Science 264: 1878–83
Kraemer SM, Kyes SA, Aggarwal G, Springer AL, Nelson SO, Christodoulou Z, et al (2007) Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates. BMC Genomics 8: 45
Su X, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JV, Peterson DS, et al (1995) A large and diverse gene family (var) encodes 200–350 kD proteins implicated in the antigenic variation and cytoadherence of Plasmodium falciparum-infected erythrocytes. Cell 82: 89–100
Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, et al (1995) Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82: 77–87
Scherf A, Hernandez-Rivas R, Buffet P, Bottius E, Benatar C, Pouvelle B, et al (1998) Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum. EMBO J 17(18): 5418–26
Chen Q, Fernandez V, Sundstrom A, Schlichtherle M, Datta S, Hagblom P, et al (1998) Developmental selection of var gene expression in Plasmodium falciparum. Nature 394(6691): 392–5
Wu Y, Kirkman L, Wellems TE (1996) Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine. Proc Natl Acad Sci USA 93: 1130–4
Deitsch KW, del Pinal A, Wellems TE (1999) Intra-cluster recombination and var transcription switches in the antigenic variation of Plasmodium falciparum. Mol Biochem Parasitol 101(1–2): 107–16
Deitsch KW, Calderwood MS, Wellems TE (2001) Malaria – cooperative silencing elements in var genes. Nature 412(6850): 875–6
Frank M, Deitsch K (2006) Activation, silencing and mutually exclusive expression within the var gene family of Plasmodium falciparum. Int J Parasitol 36(9): 975–85
Duraisingh MT, Voss TS, Marty AJ, Duffy MF, Good RT, Thompson JK, et al (2005) Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium faiciparum. Cell 121(1): 13–24
Tonkin CJ, Carret CK, Duraisingh MT, Voss TS, Ralph SA, Hommel M, et al (2009) Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum. PLoS Biol 7(4): e84
Voss TS, Healer J, Marty AJ, Duffy MF, Thompson JK, Beeson JG, et al (2006) A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria. Nature 439(7079): 1004–8
Frank M, Dzikowski R, Costantini D, Amulic B, Berdougo E, Deitsch K (2006) Strict pairing of var promoters and introns is required for var gene silencing in the malaria parasite Plasmodium falciparum. J Biol Chem 281(15): 9942–52
Dzikowski R, Frank M, Deitsch K (2006) Mutually exclusive expression of virulence genes by malaria parasites is regulated independently of antigen production. PLoS Pathog 2(3): e22
Dzikowski R, Li F, Amulic B, Eisberg A, Frank M, Patel S, et al (2007) Mechanisms underlying mutually exclusive expression of virulence genes by malaria parasites. EMBO Rep 8(10): 959–65
Dzikowski R, Deitsch KW (2008) Active transcription is required for maintenance of epigenetic memory in the malaria parasite Plasmodium falciparum. J Mol Biol 382(2): 288–97
Roberts DJ, Craig AG, Berendt AR, Pinches R, Nash G, Marsh K, et al (1992) Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature 357: 689–92
Horrocks P, Pinches R, Christodoulou Z, Kyes S, Newbold C (2004) Variable var transition rates underlie antigenic variation in malaria. Proc Natl Acad Sci USA 101(30): 11129–34
Chookajorn T, Dzikowski R, Frank M, Li F, Jiwani AZ, Hartl DL, et al (2007) Epigenetic memory at malaria virulence genes. Proc Natl Acad Sci USA 104(3): 899–902
Frank M, Dzikowski R, Amulic B, Deitsch K (2007) Variable switching rates of malaria virulence genes are associated with chromosomal position. Mol Microbiol 64(6): 1486–98
Barry AE, Leliwa-Sytek A, Tavul L, Imrie H, Migot-Nabias F, Brown SM, et al (2007) Population genomics of the immune evasion (var) genes of Plasmodium falciparum. PLoS Pathog 3(3): e34
Freitas-Junior LH, Bottius E, Pirrit LA, Deitsch KW, Scheidig C, Guinet F, et al (2000) Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407(6807): 1018–22
Frank M, Kirkman L, Costantini D, Sanyal S, Lavazec C, Templeton TJ, et al (2008) Frequent recombination events generate diversity within the multi-copy variant antigen gene families of Plasmodium falciparum. Int J Parasitol 38(10): 1099–109
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Frank, M., Enderes, C. Antigenic variation in Plasmodium falciparum: moving beyond the laboratory strains. Wien Klin Wochenschr 122 (Suppl 1), 7–10 (2010). https://doi.org/10.1007/s00508-010-1326-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00508-010-1326-0